The molecular basis underlying the salt sensitive form of essential hypertension, which is characterized as a polygenic disease with complexities such as "gene-gene" and "environment-gene" interactions, is largely unknown. The overall goal of this project is to define how sensory nerves sense changes in environment, alter its afferent and efferent activities, and interact with other systems to modulate renal function and salt sensitivity of arterial pressure. Toward this goal, we have developed a unique animal model, which shows that degeneration of vanilloid-sensitive sensory nerves impairs renal function and renders a rat salt sensitive in terms of blood pressure regulation. Our preliminary data also show that high salt intake increases expression of the vanilloid receptor (VR1) in the renal medulla, and that blockade of the VR1 increases blood pressure in rats fed a high salt diet. These observations have led to the working hypothesis which states that the VR1, expressed in a genetically distinct subpopulation of primary sensory nerves, participates in the maintenance of sodium and fluid homeostasis and plays a significant role in the long-term modulation of salt sensitivity and blood pressure. Three specific aims of the proposal will test the hypotheses: 1) that high salt intake activates renal sensory afferents via stimulation of the VR1 ; 2) that salt activates the VR1 which results in a suppression of the heightened sympathetic nerve activity occurring in response to salt load, and 3) that blockade of the VR1 impairs the adaptive response of the kidney to high salt intake and leads to increased salt sensitivity of arterial pressure. These studies represent a novel effort to define how vanilloid-sensitive sensory afferents serve as a molecular transducer for sodium and water homeostasis, as well as how "e nvironment-gene" interactions lead to salt sensitive hypertension. These data may force us to revise the ways we think about VR1 ligands. These drugs may have a much broader perspective than peripheral pain perception and may serve as specific antihypertensive compounds that can be used to selectively treat salt sensitive hypertension.